Inherited human ITK deficiency impairs IFN-γ immunity and underlies tuberculosis
0301 basic medicine
Cytotoxic T cell
Receptors, Antigen, T-Cell, alpha-beta
Human Inborn Errors
Immunology
610
Dermatology
Thymus Gland
Lymphocytosis
Article
Mice
Interferon-gamma
03 medical and health sciences
In vitro
T-Lymphocyte Subsets
Genetic Basis of Neutropenia Disorders
Biochemistry, Genetics and Molecular Biology
Receptors
616
Medicine and Health Sciences
Genetics
T lymphocyte
Animals
Humans
Tuberculosis
Immunodeficiency
Biology
alpha-beta
Immunology and Microbiology
gamma-delta
0303 health sciences
Interferon-? Pathway Defects
Genetic Basis of Primary Immunodeficiency Disorders
FOS: Clinical medicine
Lymphocytopenia
Immunity
Life Sciences
T cell
Receptors, Antigen, T-Cell, gamma-delta
CD8
T-Cell
3. Good health
[SDV] Life Sciences [q-bio]
Immune system
Antigen
FOS: Biological sciences
Lymphocyte
Natural Killer Cells in Immunity
DOI:
10.1084/jem.20220484
Publication Date:
2022-11-03T13:54:15Z
AUTHORS (44)
ABSTRACT
Inborn errors of IFN-γ immunity can underlie tuberculosis (TB). We report three patients from two kindreds without EBV viremia or disease but with severe TB and inherited complete ITK deficiency, a condition associated with severe EBV disease that renders immunological studies challenging. They have CD4+ αβ T lymphocytopenia with a concomitant expansion of CD4−CD8− double-negative (DN) αβ and Vδ2− γδ T lymphocytes, both displaying a unique CD38+CD45RA+T-bet+EOMES− phenotype. Itk-deficient mice recapitulated an expansion of the γδ T and DN αβ T lymphocyte populations in the thymus and spleen, respectively. Moreover, the patients’ T lymphocytes secrete small amounts of IFN-γ in response to TCR crosslinking, mitogens, or forced synapse formation with autologous B lymphocytes. Finally, the patients’ total lymphocytes secrete small amounts of IFN-γ, and CD4+, CD8+, DN αβ T, Vδ2+ γδ T, and MAIT cells display impaired IFN-γ production in response to BCG. Inherited ITK deficiency undermines the development and function of various IFN-γ–producing T cell subsets, thereby underlying TB.
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